The genetic architecture of defence as resistance to and tolerance of bacterial infection in Drosophila melanogaster
The genetic architecture of defence as resistance to and tolerance of bacterial infection in Drosophila melanogaster
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DOI：
10.1111/mec.14017
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发表时间：
2017-03-01
影响因子：
4.9
通讯作者：
Lazzaro, Brian P.
中科院分区：
文献类型：
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作者：
Howick, Virginia M.;Lazzaro, Brian P.
对病原体感染的防御可采取两种形式：抵抗和耐受。耐药性是宿主限制病原体负担的能力，而耐受性是将感染的负面后果限制在给定的感染强度水平的能力。在进化上，独立于抗药性的耐受策略可以使宿主避免进行代价高昂的免疫反应，理论上，还可以避免病原菌毒力和宿主抗药性之间的共同进化军备竞赛。在生物医学上，了解耐受机制及其与耐药性的关系可能会产生专注于改善健康而不是消除病原体的治疗策略。为了了解耐受性对寄主防御的影响并确定决定寄主耐受性的遗传变异，我们将耐受性的遗传变异定义为在感染强度下适应度的二项回归的残差。然后，我们进行了全基因组关联研究，以绘制对Presdencia rettgeri细菌感染的抵抗力和耐受性变异的遗传基础。我们发现抗性和耐受性之间存在正的遗传相关，并且我们证明了抗性水平对耐受性有很高的预测作用。我们确定了30个预测耐受性的基因座，其中许多位于参与免疫和新陈代谢调节的基因中。我们使用RNAi来确认映射的基因的子集在防御中发挥作用，包括假定的伤口修复基因颗粒状头部和碎片破坏者。我们的结果表明，耐受不是一种独立于抵抗的策略，而是一系列与规范免疫和抵抗交织在一起的生理过程产生的防御。
Defence against pathogenic infection can take two forms: resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, whereas tolerance is the ability to limit the negative consequences of infection at a given level of infection intensity. Evolutionarily, a tolerance strategy that is independent of resistance could allow the host to avoid mounting a costly immune response and, theoretically, to avoid a co-evolutionary arms race between pathogen virulence and host resistance. Biomedically, understanding the mechanisms of tolerance and how they relate to resistance could potentially yield treatment strategies that focus on health improvement instead of pathogen elimination. To understand the impact of tolerance on host defence and identify genetic variants that determine host tolerance, we defined genetic variation in tolerance as the residual deviation from a binomial regression of fitness under infection against infection intensity. We then performed a genomewide association study to map the genetic basis of variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and tolerance, and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that predict tolerance, many of which are in genes involved in the regulation of immunity and metabolism. We used RNAi to confirm that a subset of mapped genes have a role in defence, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defence arises from a collection of physiological processes intertwined with canonical immunity and resistance.